Spinal and bulbar muscular atrophy (SBMA) is a late onset, neurodegenerative disease that affects 1 in 40,000 men. It is caused by a polymorphic trinucleotide-expansion in the androgen receptor gene that encodes a polyglutamine tract in the protein. This polyglutamine tract confers a toxic property to the AR through an unknown mechanism. It has recently been shown that an interdomain interaction of the AR between the amino- terminal FxxLF motif and the carboxyl-terminal AF2 domain (N/C interaction) is necessary for toxicity in a PC12 cell model of disease. Preventing this interaction, either by genetically mutating the FxxLF motif or through pharmacological inhibition rescues a PC12 cell model of disease from AR aggregation and cell death. However, the mechanism by which blocking this interaction prevents disease is unknown. The goal of the proposed studies is to better understand the N/C interaction of the AR in the context of SBMA. These in vitro results suggesting that the N/C interaction is necessary for toxicity will be validated in a novel transgenic mouse model that expresses polyglutamine expanded AR with a mutated FxxLF motif that prevents the N/C interaction. The effect this mutation has on disease onset and progression will be determined by comparing phenotypes of this mouse model with those observed in a transgenic mouse model of SBMA that recapitulates many hallmarks of the human disease. Ser-81 phosphorylation, which is a marker of the N/C interaction, is increased in polyglutamine- expanded AR suggesting an increase in this interaction. FRET imaging will be used to investigate if the N/C interaction is altered in polyglutamine-expanded AR compared to normal AR. Additionally, the mechanism through which blocking the N/C interaction decreases aggregation and toxicity of polyglutamine-expanded AR is unknown. We observed that Ser-16 phosphorylation is increased when the N/C interaction is blocked. Since the phosphorylation status of proteins can have a significant role in modulating toxicity in other polyglutamine diseases, Ser-16 phosphorylation is a candidate for modulating toxicity in SBMA. Its role in the decreased toxicity associated with blocking the N/C interaction will be examined. These mechanistic studies will help to better understand the pathogenesis of SBMA and to develop novel targets for therapeutic development.